Inflammation-preventing pharmaceutical composition of oral administration

ABSTRACT

A novel pharmaceutical composition is provided which is suitable for the prevention of inflammation and which comprises non-steroidal inflammation-preventing compound (e.g. pyrazolones, salicylic acid derivatives, indoles, indanes, and phenylacetic acid and anthranilic acid derivatives) and at least one phospholipid.

BACKGROUND OF THE PRESENT INVENTION

A great number of substances for the effective treatment of inflammatory illnesses, for example rheumatism, have been known for a long time. Since the inflammations are often chronic, the treatment with such inflammation-preventing active substances will usually extend over a long period of time. The non-steroidal antiphlogistic substances used for such continuous treatments very often have undesirable side effects on the digestive tract, such as, for example, in the form of gastro-intestinal bleeding and stomach ulcers as described by Y. H. Lee et al in "Arch. int. Pharmacodyn." 191, 370-377 (1971) and by K. D. Rainsford in "Agents and Actions" 1977 7(5/6), 573-77, as well as by A. R. Cooke in "Drugs" 1976, vol. 11, pages 36 to 44.

Many attempts have been made to moderate the side effects of these effective non-steroidal antiphlogistic substances by the admixture of an additional active substance. All mixtures of this type have the disadvantage that the additional substance might cause an ulcer on its own, or might even influence adversely the effectiveness of the primary non-steroidal antiphlogistic substance.

Attempts have been made, for example, to admix anticholinergic substances or pepsin inhibitors with the antiphlogistic substances (Y. H. Lee et al, "Arch. int. Pharmacodyn," 191, 370-377 (1971)). The firm of Richter Gedeon (DE-OS No. 25 24 902) proposed the admixture of salicylic acid salts with the antiphlogistic substances. However, salicylic acid salts have analgetic and antiphlogistic properties of their own and can cause strong side effects such as nausea and vomiting as well as damage of the mucous membrane of the stomach with the possibility of bleeding if administered over longer periods of time as reported by E. Mutschler in "Arzneimittelwirkungen", wissenschaftliche Verlagsgesellschaft 1970, pages 76, 77.

The Sumitomo Chemical Co. Ltd. has proposed the combination of non-steroidal antiphlogistic substances with quinazolines (see DE-OS No. 26 27 914) with the purpose of preventing the formation of peptic ulcers within the area of the digestive tract. However, these quinazolines are substances with an analgetic and antiphlogistic effect of their own. U.S. Pat. No. 3,993,767 describes mixtures of non-steroidal antiphlogistic substances with metaxalon. However, the metaxalon has a muscle-relaxing effect. See the Merck Index, Ninth edition 1976, page 772.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefor the object of the present invention to develop an inflammation-preventing medicine which will substantially improve the poor compatibility of non-steroidal antiphlogistic substances without adversely influencing the inflammation-preventing effect of these active substances.

It has been found that serious side effects on the digestive tract such as damage to the mucous membrane or gastric ulcer formation by non-steroidal antiphlogistic substances can be prevented if these substances are combined in a suitable manner with phospholipids. The medicinal compositions of the present invention will therefore contain these antiphlogistic substances in conjunction with phospholipids. The phospholipids have the advantage over the previously described substances in that they are body-inherent, can be readily broken down within the body, do not promote any side effects (even if administered continuously (see J. Weihrauch, U.S. Dept. of Agriculture, quoted in National Enquirer of June 6, 1978, page 33)) and do not possess any analgetic or antiphlogistic effect of their own. The admixture of phospholipids with non-steroidal antiphlogistic substances substantially lowers the degree of side effects while the analgetic and antiphlogistic properties remain intact.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Natural as well as synthetic phospholipids can be used in the preparations of the present invention. Natural phospholipids (of plant or animal origin) such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, sphingomyeline, cephaline, lysolecithin, phosphatidylglycol, cardiolipin, and plasmalogens (which can all be obtained, for example, from the soya bean or egg) and mixtures of these phospholipids are suitable for use in the present invention. Commercially available phosphatidylcholines or phosphatidylcholine-mixtures include Phospholipon® 100, Phospholipon® 100 H, Phospholipon® 80 and Phospholipon® 45. Usable synthetic phosphatides include, for example, ditetradecanoylphosphatidylcholine, dihexadecanoylphosphatidylcholine, dioleylphosphatidylcholine or dilinolylphosphatidylcholine and especially dipalmitoylphosphatidylcholine.

The following substances are especially suitable non-steroidal antiphlogistic substances for use in the combination proposed by the invention:

Pyrazolones and especially

phenylbutazone (4-butyl-1,2-diphenylpyrazolidine-3,5-dion), and

oxyphenbutazone (4-butyl-2-(4-hydroxyphenyl)-1-p-phenylpyrazolidine-3,5-dion);

Salicylic acid derivatives such as salicylic acid

salicylic acid amide,

acetyl-salicylic acid,

benorilate (4-acetamidophenyl-o-acetylsalicylate), and

diflunisal (5-(2,4-difluorophenyl)-salicylic acid);

Indoles, especially indometacine and its analogs such as

indometacine (1-(p-chlorobenzyyl)-5-methoxy-2-methylindole acetic acid),

glucametacine (1-(p-chlorobenzoyl-5-methoxy-2-methylindole-3-yl acetic acid glucose amide),

acemetacine (1-(p-chlorobenzoyl)-5-methoxy-3-methylindole-3-acetic acid-glycolic acid-ester), and

sulindac (5-fluor-2-methyl-1-p-(methylsulphenyl)benzylidene-indene-3-acetic acid);

Phenyl acetic acid or phenyl propionic acid derivatives such as

ibuprofen (2-(4-isobutylphenyl)-propinic acid);

naproxen (2-(6-methoxy-2-naphthtyl)-propinic acid),

alclofenac (4-allyloxy-3-chlorophenyl-acetic acid),

ketoprofen (2-(3-benzylphenyl)-benzoic acid),

diclofenac (2-(2,6-dichlorophenylamino)-phenylacetic acid),

fenoprofen (2-(3-phenyloxyphenyl)-acetic acid),

tolmetin (1-methyl-5-(p-toluyl)-pyrrole-2-yl-acetic acid),

flurbiprofen (2-(2-fluorobiphenyl-4-ye-propionic acid), and

suprofen (p-2-thenoyl-hydratropic acid) phenylproprionic acid);

Anthranilic acids and their nitrogen analogs such as flufenamino acid (N-(m-trifluoromethylphenyl)anthranilic acid),

mefenamino acid (N-(2,3-dimethylphenyl)-anthranilic acid), and

niflumin acid (2-(3-trifluoromethylaminolino)nicotinic acid).

The novel mixture of the present invention comprising non-steroidal antiphlogistic substances and phospholipid is particularly suitable for oral application where the molar ratio of antiphlogistic substance to phospholipid ranges from about 1:0.1 to about 1:20, and preferably from about 1:0.5 to about 1:2.

The mixture can be prepared by dissolving the antiphlogistic substance and the phospholipid in a suitable organic solvent such as methanol, ethanol or chloroform and by subsequently separating the solvent from the mixture by distillation. The antiphlogistic substance can also be dissolved in water at a suitable pH with the phospholipid being stirred into the solution. The emulsion or solution so obtained is then freed of water by lyophilic treatment, with a loose powder being obtained thereby.

The mixtures prepared in this manner can be further processed into medicines of the various standard forms of application such as, for example, in the form of pills, filled into a capsule or dispensed in the form of a granulate, a powder or a suspension. The medicine can further contain the usual quantities of carrier materials and/or diluents as well as auxiliary substances such as starch, gelatine, agar, sugar, carboxy-methylcellulose, polyvinylalcohol, magnesium stearate, sodium alginate and the like.

The advantageous effectiveness of the novel medicines proposed by the invention is demonstrated by several pharmacological tests which are listed below. The development of the ulcer was determined in accordance with

B. J. R. Whittle, "Brit. J. Pharmakol." 55, 242-243 (1975),

L. Mariani, "Eur. J. Toxicol. Environ." 8, 335-339 (1975), and

R. Menguy & L. Desbaillets, "Proc. Soc. exp. Bio." 125, 1108.

Ten male and ten female Wistar-rats (120 to 150 grams, in weight) which have not fed for 16 hours, were used for these tests. The bleeding stomach ulcer was provoked by oral application of the active substance. After 3.5 hours, the animals are killed and the stomach extracted, opened along the wide curvature and stretched onto a "Styropor" plate. The mean ulcer factor of the test and of the control group are determined. The variation is weighted in percentages as prevention of the ulcer formation.

    ______________________________________                                         Reference substances:                                                          ______________________________________                                         chloropromazine                                                                               oral ED50 = 104.82 mg kg/KGW                                    atropinesulphate                                                                              oral ED50 =  17.06 mg kg/KGW                                    ______________________________________                                    

The results of the tests are tabulated below in Tables I to VI:

                                      TABLE I                                      __________________________________________________________________________     Influence of Phospholipon® 100 Upon Ulcer Development                      Oral Application of Acetyl-Salicylic Acid                                      (Molar Ratio of Acetyl-Salicylic Acid:Phospholipon = 2:1)                                                  Variation of the Mean                                                          Ulcer Factor :                                                        Acetyl-Salicylic                                                                        Acetyl-Salicylic Acid                              Dosage    Acetyl-Salicylic                                                                        Acid With p.sup.+                                                                       With p.sup.+ Versus                                                                       Incidence of                            (mg/kg KGW)                                                                            n Acid Ulcer Index.sup.a                                                                  Ulcer Index.sup.a                                                                       Without p.sup.+  (%)                                                                      Ulcers (%)                                                                            p-Value                          __________________________________________________________________________     200     10                                                                               1.20 ± 0.20                                                                          0.30 ± 0.09                                                                          -83.33     70 resp. 20                                                                           0.001                            400     10                                                                               1.10 ± 0.50                                                                          0.70 ± 0.06                                                                          -36.36     50 resp. 70                                                                           0.10-0.01                        800     10                                                                               1.20 ± 0.20                                                                          0.70 ± 0.06                                                                          -41.67     80 resp. 70                                                                           0.01-0.001                       __________________________________________________________________________      p.sup.+  = Phospholipon® 100 (92% Phosphatidylcholin, 4%                   Lysophosphatidylcholin, 3% Neutrallipide, 1% water).                           .sup.a -x ± s.sub.x --                                                

                                      TABLE II                                     __________________________________________________________________________     Influence Upon Ulcer Development By Phospholipon® 100 With                 Oral Application of Phenylbutazone                                             (Molar Ratio of Phenylbutazone : Phospholipon = 2:1)                                                        Variation of Mean                                                              Ulcer Factor :                                                                 Phenylbutazone                                    Dosage    Phenylbutazone                                                                         Phenylbutazone                                                                            With p.sup.+  Versus                                                                    Incidence of                             (mg/kg KGW)                                                                            n Ulcer Index.sup.a                                                                      With p.sup.+ Ulcer Index.sup.a                                                            Without p.sup.+  (%)                                                                    Ulcers (%)                                                                            p-Value                           __________________________________________________________________________     25      10                                                                               0.70 ± 0.05                                                                         0.30 ± 0.04                                                                            -57.14    70 resp. 30                                                                          0.02-0.01                         50      10                                                                               1.60 ± 0.42                                                                         0.90 ± 0.42                                                                            -43.75    60 resp. 40                                                                          0.01-0.001                        100     10                                                                               1.80 ± 0.84                                                                         1.20 ± 0.84                                                                            -33.33   100 resp. 90                                                                          0.02-0.01                         200     10                                                                               1.90 ± 0.66                                                                         1.20 ± 0.96                                                                            -36.84   80     0.01-0.001                        __________________________________________________________________________      p.sup.+  = Phospholipon® 100 (as previously defined)                       .sup.a -x ± s.sub.x --                                                

                                      TABLE III                                    __________________________________________________________________________     Influence Upon Ulcer Development By Phospholipon® 100                      With Oral Application of Indometacine                                          (Molar Ratio Indometacine : Phospholipon = 1:2)                                                            Variation of Mean                                                              Ulcer Factor:                                                                  Indometacine                                       Dosage    Indometacine                                                                          Indometacine                                                                              With p.sup.+ and                                                                        Incidence of                              (mg/kg KGW)                                                                            n Ulcer Index.sup.a                                                                     With p.sup.+ Ulcer Index.sup.a                                                            Without (%)                                                                             Ulcers (%)                                                                            p-Value                            __________________________________________________________________________     5       10                                                                               1.20 ± 0.30                                                                        0.20 ± 0.31                                                                            -83.33   70 resp. 20                                                                           0.02-0.01                          10      10                                                                               1.90 ± 0.90                                                                        0.40 ± 0.07                                                                            -78.95   90 resp. 40                                                                           0.001                              20      10                                                                               1.50 ± 0.40                                                                        0.50 ± 0.08                                                                            -66.67   100 resp. 50                                                                          0.001                              __________________________________________________________________________      p.sup.+ = Phospholipon® 100 (as previously                                 .sup.a -x ± s.sub.x--                                                 

                                      TABLE IV                                     __________________________________________________________________________     Influence Upon Ulcer Development By Phospholipon® 45                       of a Rat With Oral Application of Indometacine                                 (Molar Ratio of Indometacine : Phospholipon = 1:2)                                                        Variation of Mean                                                              Ulcer Factor:                                                                  Indometacine                                        Dosage    Indometacine                                                                          Indometacine With                                                                        With p.sup.+ and                                                                        Incidence of                               (mg/kg KGW)                                                                            n Ulcer Index.sup.a                                                                     Phospholipon® 45.sup.a                                                               Without (%)                                                                             Ulcers (%)                                                                            p-Value                             __________________________________________________________________________     5       10                                                                               2.10 ± 0.36                                                                        1.20 ± 0.29                                                                           -42.85   80 resp. 90                                                                           0.1-0.05                            10      10                                                                               2.20 ± 0.42                                                                        1.80 ± 0.25                                                                           -18.18   90     0.5-0.4                             20      10                                                                               2.30 ± 0.47                                                                        2.00 ± 0.36                                                                           -13.04   100    0.5                                 30      10                                                                               2.70 ± 0.30                                                                        2.40 ± 0.30                                                                           -11.11   80 resp. 100                                                                          0.5-0.4                             __________________________________________________________________________      p.sup.+ = Phospholipon® 45 (45% Phosphatidylcholine, 25%                   Phosphatidylethanolamine, 12% Phosphatidylinositol, 10% Sterine, 4%            Lysophosphatidylcholine and Lysophosphatidylcholinethanolamine, 3%             Neutrallipide, 1% water)                                                       .sup.a -x ± s.sub.x--                                                 

                                      TABLE V                                      __________________________________________________________________________     Influence Upon Ulcer Development By Phospholipon® 100                      With Oral Application of Indometacine                                          (Dosage One cc per mg/kg of Body Weight (KGW))                                                                Variation of Mean Ulcer Factor :                Proportion of Indometacine :                                                                 Indometacine                                                                          Indometacine With                                                                        Indometacine With p.sup.+ Versus                Phospholipon® 100                                                                        Ulcer Index.sup.a                                                                     p.sup.+  Ulcer Index.sup.a                                                               Without p.sup.+ (%)                             __________________________________________________________________________     1:0           2.60 ± 0.22                                                                        --        ±0                                           1:0.1         --     1.70 ± 0.21                                                                           -34.62                                          1:2.0         --     0.40 ± 0.07                                                                           -78.95                                           1:10.0       --     1.60 ± 0.16                                                                           -38.46                                          __________________________________________________________________________      p.sup.+ = Phospholipon® 100 (as previously defined)                        .sup.a -x ± s.sub.x --                                                

                                      TABLE VI                                     __________________________________________________________________________     Influence Upon Ulcer Development By Phospholipon® 100                      of a Rat With Oral Application of Ibuprofen                                    (Molar Ratio Ibuprofen : Phospholipon = 1:1)                                                                 Variation of Mean                                                              Ulcer Factor :                                                                 Ibuprofen With p.sup.+                           Dosage    Ibuprofen                                                                             Ibuprofen Ulcer Index.sup.a                                                                 and       Incidence of                           (mg/kg KGW)                                                                            n Ulcer Index.sup.a                                                                     With Phospholipon® 100                                                                  Without p.sup.+  (%)                                                                     Ulcers (%)                                                                            p-Value                         __________________________________________________________________________      5      10                                                                               0.20 ± 0.13                                                                        0.20 ± 0.13                                                                              ±0     20     0.5                             10      10                                                                               0.30 ± 0.15                                                                        0.20 ± 0.13                                                                              -33.30    20 resp. 30                                                                           0.5                             20      10                                                                               0.50 ± 0.22                                                                        0.40 ± 0.16                                                                              -20.00    40 resp. 50                                                                           0.5                             30      10                                                                               0.71 ± 0.30                                                                        0.50 ± 0.22                                                                              -28.57    50 resp. 70                                                                           0.5                             __________________________________________________________________________      p.sup.+  = Phospholipon® 100 (as previously defined)                       .sup.a -x ± s.sub.x --                                                

The antiphlogistic effectiveness was determined in accordance with the rat-paw-oedema test proposed by Hillebrecht (J. Hillebrecht, "Arzneimittelforschung", 4, 607 (1954).

On one hind paw of each rat (weight 200 to 250 grams) an oedema was caused to develop by the "subplantane" application of carragenin (0.5% in a 0.9% NaCl solution) in the amount of 0.1 ml solution per paw.

After the application of the test substance, its volume not to exceed 10 ml per kg of body weight, the volume of the paw is determined in an overflow ("Ueberlauf"). After three hours the final value is ascertained. The test is carried out for every dosage by using 10 test and 10 control animals of one sex and repeated with the identical number of animals of the other sex. For the purpose of evaluation, the prevention of the oedema is expressed in percentages relative to the control group.

    ______________________________________                                         Reference substances:                                                          ______________________________________                                         Hydrocortisoneacetate                                                                         oral ED50 =  19.00 mg/kg/KGW                                    phenylbutazone oral ED50 = 100.00 mg/kg/KGW                                    indometacine   oral ED50 =  7.24 mg/kg/KGW                                     ______________________________________                                    

The results of these tests are listed below in Tables VII and VIII:

                  TABLE VII                                                        ______________________________________                                         Comparison of the Effectiveness of Indometacine                                and an Indometacine-Phospholipon® 100 Mixture                              Applied to Rat-Paw Oedema                                                      Indometacine                                                                            Phospholipon® 100                                                                         Prevention of                                                                             Number of                                   (mg/kg p.o.)                                                                            mg/kg p.o.     Oedema (%) Animals                                     ______________________________________                                         3.16     --             -47.3      12                                          10       --             -37.8      12                                          3.16     7.1            -39.3      12                                          10       22.4           -35.7      12                                          --       100            -4.1       18                                          ______________________________________                                    

                  TABLE VIII                                                       ______________________________________                                         Comparison of the Effectiveness of Indometacine                                and Indometacine-Phospholipon® 100 Mixtures                                Applied to Rat Paw Oedema (Dosage 0.0 mg/kg                                    KGW, 12 Animals)                                                               Time:Hours Elapsed       Indometacine-Phosphol-                                After Application        ipon® 100 Molar Ratios                            of Active Substance                                                                         Indometacine                                                                               1:0.1   1:1   1:10                                    ______________________________________                                         3            32          33      55    32                                      4            40          28      41    45                                      5            28          24      26    24                                      6            27          24      32    38                                      ______________________________________                                    

The invention is additionally illustrated in connection with the following Examples which are to be considered as illustrative of the present invention. It should be understood, however, that the invention is not limited to the specific details of the Examples.

EXAMPLE 1

4.2 grams of phenylbutazone (13.6 mMol) are suspended in 75 ml of water and admixed with 13.5 ml of caustic soda solution. Into the clear solution so obtained there are stirred 5.45 gram (7.8 mMol) of Phospholipon® 100. The emulsion so obtained is treated lyophilically. The crystals produced are mixed with suitable additives, pressed into pills or filled into capsules.

EXAMPLE 2

1.5 grams (4.2 mMol) of indometacine are processed in a manner similar to that set forth in Example 1 to form a mixture with 4.1 of caustic soda solution, 40 ml of water and 3.35 gram (4.2 mMol) of Phospholipon® 45 and then treated lyophilically.

EXAMPLE 3

1.88 grams (10 mMol) of acetyl-salicylic acid, 10 ml of caustic soda solution, 25 ml of water and 4 grams (5 mMol) of Phospholipon® 100 are processed into a mixture and are then treated lyophilically.

EXAMPLE 4

Similar to Example 1, 1.88 grams (10 mMol) of acetyl-salicylic acid, 1.46 grams of DL-lysine, 30 ml of water and 1.6 grams (2 mMol) of Phospholipon® 100 are processed into a mixture and then treated lyophilically.

EXAMPLE 5

1.43 grams (4 mMol) of indometacine and 3.2 grams (4 mMol) of Phospholipon® 100 are dissolved in 50 ml of heated ethanol. The ethanol is then separated by distillation. The remaining substance is mixed with suitable additives pressed into pills or filled into capsules.

EXAMPLE 6

Acetyl-salicylic acid pills:

acetyl-salicylic acid: 216 mg

Phospholipon® 100: 400 mg

aerosil: 50 mg

Na-carboxymethylcellulose: 16 mg

Cuttina H®: 12 mg

microcrystalline cellulose: 150 mg

The substances listed above are mixed, pressed and the items so pressed are coated in a manner known per se with 20 mg of hydroxypropylmethylcellulosephthalate in a coating drum.

EXAMPLE 7

Acetyl-salicylic acid capsules:

acetyl-salicylic acid: 108 mg

Phospholipon® 80: 200 mg

talcum: 3 mg

magnesiumstearate: 3 mg

microcrystalline cellulose: 100 mg

aerosil: 25 mg

The substances listed above are granulated and filled into capsules (500 mg hard-gelatin capsules).

In the case of the Examples 8-13, pills and capsules are manufactured in a manner similar to the Examples 1, 2 and 3 but employing other non-steroid, inflammation-preventing substances.

EXAMPLE 8

An indometacine pill is produced from:

30 mg of indometacine and

130 mg of Phospholipon® 100

EXAMPLE 9

An indometacine pill is produced from:

30 mg of indometacine and

70 mg of Phospholipon® 100H

EXAMPLE 10

Indometacine capsules are produced containing:

30 mg of indometacine

130 mg of Phospholipon® 100

EXAMPLE 11

Phenylbutazone pills are produced containing:

105 mg of phenylbutazone

140 mg of Phospholipon® 100

EXAMPLE 12

Ibuprofen pills are produced containing:

100 mg of ibuprofen

210 mg of Phospholipon® 100

EXAMPLE 13

Acetyl-salicylic acid pills are produced containing:

220 mg of acetyl-salicylic acid

80 mg of dipalmitoylphosphatidylcholine

All the preparations of Examples 8-13 show an improvement in compatibility and prevented side effects which normally are occurring in connection with the active substances involved.

The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art without departing from the spirit of the invention. 

What is claimed is:
 1. A method of alleviating inflammation in a mammal comprising orally administering to said mammal an effective inflammation-alleviating amount of a pharmaceutical composition comprising a phospholipid and a non-steroidal inflammation-preventing indole in a molar ratio ranging from about 0.1:1 to about 20:1, respectively.
 2. The method of claim 1 wherein said indole is selected from the group consisting of indometacine, glucametacine, and acemetacine.
 3. The method of claim 2 wherein said indole is indometacine.
 4. The method of claim 2 wherein said indole is acemetacine.
 5. The method of claim 1 wherein said phospholipid and said indole are present in molar ratios ranging from about 0.5:1 to about 2:1.
 6. The method of claim 1 wherein said phospholipid is phosphatidylcholine.
 7. The method of claim 1 wherein said phospholipid is phosphatidylinositol.
 8. A pharmaceutical composition in a form for oral administration in the prevention of inflammation in mammals comprising an effective inflammation-alleviating amount of a phospholipid and a non-steroidal inflammation-preventing indole in a molar ratio ranging from about 0.1:1 to about 20:1, respectively.
 9. The pharmaceutical composition of claim 8, wherein said indole is selected from the group consisting of indometacine, glucametacine, and acemetacine.
 10. The pharmaceutical composition of claim 9 wherein said indole is indometacine.
 11. The pharmaceutical composition of claim 9 wherein said indole is acemetacine.
 12. The pharmaceutical composition of claim 8 wherein said phospholipid and said indole are present in molar ratios ranging from about 0.5:1 to about 2:1.
 13. The pharmaceutical composition of claim 8 wherein said phospholipid is phosphatidylchloine.
 14. The pharmaceutical composition of claim 8 wherein said phospholipid is phosphatidylinositol. 